During the first six years of this research program, a comprehensive qualitative and quantitative characterization of the effects of marginal zinc deficiency on the developing nonhuman primate has been achieved. We are now able to focus on hypotheses concerning the mechanisms of these effects. Continuing work with pregnant and developing monkeys will be directed at three issues important to this problem: (1) identification of the most vulnerable developmental periods; (2) evaluation of plasma metallothionein (mt) as a rapid and accurate index of zinc status; (3) metabolic interactions of marginal zinc deprivation with drugs and supplements. These goals are integrated into two experiments to be completed, over a five year period. As a result of these studies, a strong scientific basis for recognizing, preventing and treating adverse health effects of this important trace element will be provided. This work is important because zinc deprivation can have significant effects during pregnancy and child development. However, there are few definitions of specific factors and mechanisms involved in the influences of zinc on maternal and child health, including aspects of growth, development, behavior or immune function. Although zinc deficient mothers may be considered to be "nutritionally-at- risk" for normal fetal development, it is unclear why there are individual differences and to what extent interactions of zinc with other factors might contribute to this problem. Finally, plasma zinc remains a reltively poor indicator of zinc nutriture and better markers for zinc status, i.e., indices suitable for rapid estimation need to be determined. Specifically, we will characterize zinc absorptiona and metabolism in pregnant monkeys and identify zinc interactions which might contribute to being "nutritionally-at-risk"; this includes detailed kinetic and metabolic interactions of zinc and iron and zinc and valproic acid. We will prepare antibodies to plasma mt and monitor animals fed control and marginally zinc deficient diets for mt as well as several other potential markers of zinc status to determine an appropriate and valid marker for a rapid estimation of zinc status. We believe that new diagnostic tools are needed to identify nutritionally-at-risk mothers since clinical observations and plasma zinc levels have proven inadequate in this regard. We believe, following completion of this study, that we will have much better concepts of the mechanisms involved in zinc interactions, through our intensive studies of zinc metabolism in vitro and at the tissue level.